Epigenetic Modifications of BDNF and trkB Genes Underlie Pain Plasticity

BDNF 和 trkB 基因的表观遗传修饰是疼痛可塑性的基础

基本信息

批准号：
8711108
负责人：
SUSAN G DORSEY
金额：
$ 56.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-28 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711108
关键词：
AIDS/HIV problem Acute Affect American Analgesics Animals Anti-Retroviral Agents Behavior Behavioral Benefits and Risks Biological Markers Brain-Derived Neurotrophic Factor Candidate Disease Gene Chromatin Chromatin Structure Chronic Chronic Disease Cisplatin Complex Complication DNA DNA Methylation DNA Methyltransferase Inhibitor Data Development Disease Dose Dose-Limiting Drug usage Epidemic Epigenetic Process Gene Expression Genes Genome HIV Hippocampus (Brain)Hypersensitivity Inbred Strains Mice Individual Life Expectancy Link Malignant Neoplasms Memory Methods Methylation Modification Molecular Molecular Target Mus Neuropathy Neurotrophic Tyrosine Kinase Receptor Type 2 Nociception Paclitaxel Pain Pain Research Pain management Patients Persistent pain Pharmaceutical Preparations Pharmacological Treatment Phenotype Physiological Posterior Horn Cells Pre-Clinical Model Predisposition Productivity Promoter Regions Public Health Quality of life Receptor Protein-Tyrosine Kinases Regimen Regulation Resistance Role Sampling Spinal Spinal Cord Stavudine Stimulus Symptoms Testing Therapeutic Translating Up-Regulation Work behavior change central sensitization chemotherapeutic agent chemotherapy chromatin immunoprecipitation chronic pain cost dorsal horn drug development epigenome genetic manipulation histone modification human subject improved in vivo long term memory mRNA Expression neuron development next generation sequencing novel oxaliplatin pain behavior painful neuropathy prevent protein expression public health relevance research study stem

项目摘要

DESCRIPTION (provided by applicant): Although we are at the end of the Congressionally-declared Decade for Pain Control and Research, chronic pain continues to be a leading public health epidemic, affecting more than 50 million Americans and costing more than $165 billion per year in treatment expenses and lost work productivity. Of particular note are those patients with chronic diseases, such as cancer and HIV, who suffer from treatment-related pain that cannot be controlled with conventional analgesics. Treatment-related pain affects approximately 50% of these patients, depending on drug and dosing regimen, which translates into nearly 700,000 Americans per year. The predominant symptom is excruciating unremitting pain that is resistant to traditional pharmacological treatments. As therapeutics become increasingly aggressive and diseases become chronic, this becomes a risk/benefit issue; patients must choose between increased life expectancies and constant suffering with decreased quality of life. This decision is untenable, and thus, the crucial question that must be answered is how to prevent or reverse persistent disease treatment-related pain. Recent mechanistic studies have found that the development and persistence of neuropathic pain stems in part from central sensitization in the spinal dorsal horn. Much like memory formation in the hippocampus, central sensitization in the spinal cord produces pain hypersensitivity that is uncoupled from noxious input. More simply put, innocuous inputs produce long lasting pain hypersensitivity. Recently, we made the preliminary discovery that antiretroviral treatment produces up-regulation of Brain-derived Neurotrophic Factor (BDNF) in the mouse spinal dorsal horn, causing central sensitization (hyperexcitability of spinal dorsal horn neurons) and the development and persistence of nocifensive (pain) behavior. Reducing levels of BDNF expression in vivo reversed this phenotype. These data implicating BDNF in treatment-related pain suggest that BDNF may represent a new target for drug development. However, further studies to determine precisely how chemotherapeutic drugs alter BDNF expression and that of the BDNF receptor, tyrosine kinase receptor B (trkB) are crucial first steps. One likely possibility is via epigenetic regulation of BDNF and trkB gene expression. In support of this idea, we have shown that alterations in DNA methylation and histone modifications in promoter regions produce changes in BDNF gene expression that regulate the capacity for long-term memory formation. Thus, we hypothesize that complex epigenetic regulation of BDNF and trkB may produce gene dysregulation that is mechanistically linked to long-term chemotherapy-induced neuropathic pain. In addition, we posit that other genes, not previously linked with nociception, may undergo epigenetic regulation and we will examine this question using chromatin immunoprecipitation (ChIP) followed by high-throughput next generation sequencing (ChIP-seq). Results from these studies will have broad impact beyond treatment-related pain to improve our understanding of chronic pain persistence and the role for epigenetic modifications.

描述（由申请人提供）：尽管我们正处于疼痛控制和研究的国会期末十年的结束，但慢性疼痛仍然是领先的公共卫生流行病，影响了超过5000万美国人，并且每年的治疗费用损失了超过1650亿美元的治疗费用和失去工作效率。特别值得注意的是那些患有慢性疾病的患者，例如癌症和艾滋病毒，他们患有与治疗相关的疼痛，无法用常规镇痛药控制。与治疗相关的疼痛会影响这些患者的大约50％，具体取决于药物和给药方案，每年转化为近70万美国人。主要的症状是使对传统药理治疗具有抗性的不易疼痛。随着治疗剂变得越来越侵略性并变得长期疾病，这成为一个风险/利益问题；患者必须在预期的增加和持续的苦难之间选择，生活质量降低。这一决定是站不住脚的，因此，必须回答的关键问题是如何预防或逆转持续性疾病治疗相关的疼痛。最近的机械研究发现，神经性疼痛的发育和持续性部分源于脊髓背角的中央敏化。就像海马中的记忆形成一样，脊髓中的中央敏化会产生与有害输入无关的疼痛超敏反应。简而言之，无害的输入会产生持久的疼痛超敏反应。最近，我们提出了一个初步发现，即抗逆转录病毒治疗会在小鼠脊髓背角中产生脑衍生的神经营养因子（BDNF）的上调，从而导致中心敏化（脊柱背角神经元过度敏感）以及综合性（疼痛）行为的发育和持久性。体内降低BDNF表达水平逆转了这种表型。这些暗示BDNF在治疗相关疼痛中的数据表明，BDNF可能代表了药物开发的新目标。然而，进一步的研究以确定化学治疗药物如何改变BDNF表达和BDNF受体，酪氨酸激酶受体B（TRKB）是至关重要的第一步。一种可能的可能性是通过BDNF和TRKB基因表达的表观遗传调节。为了支持这一想法，我们已经表明，启动子区域中DNA甲基化和组蛋白修饰的改变会导致BDNF基因表达的变化，从而调节长期记忆形成的能力。因此，我们假设BDNF和TRKB的复杂表观遗传调节可能会产生基因失调，这与长期化学疗法诱导的神经性疼痛有关。此外，我们认为其他基因以前与伤害感受联系在一起，可能会进行表观遗传调节，我们将使用染色质免疫沉淀（CHIP）检查这个问题，然后进行高通量下一代测序（CHIP-SEQ）。这些研究的结果将在与治疗相关的疼痛之外产生广泛的影响，以提高我们对慢性疼痛持久性的理解和表观遗传修饰的作用。